Recent reports suggest that survivors of pediatric brain tumor are at increased risk of cardiovascular disease (1–4). As obesity is a well-known risk factor for the development of cardiovascular disease in the general population, this might provide a potential explanation of the added cardiometabolic risk in survivors of pediatric brain tumor (5). However, when obesity rates are analyzed based on body mass index (BMI), pediatric brain tumor patients are observed to have BMI levels similar to the general population, which is not likely to explain the observed increased risk of cardiovascular disease in pediatric brain tumor survivors (6, 7). Furthermore, as BMI is simply a measure of mass, standardized by height, it does not detail the type of the tissue present in a body. For example individuals with above-average lean (muscle) mass are frequently classified as overweight/obese, irrespective of their level of adiposity. Accordingly, more scientifically valid means of assessing body composition are available such as Dual X-ray Absorptiometry (DXA) (8, 9).

Childhood-onset craniopharyngiomas are rare malformations of embryonal origin with low-grade histological malignancy [World Health Organization (WHO) grade 1] located in the sellar/parasellar area and frequently affecting hypothalamus, pituitary gland and optic chiasm (10–12). Tumor- and/or treatment-related damage to these anatomical areas result in reduced physical and psychosocial function (13), which includes clinically severe neuroendocrine adverse effects, mainly hypothalamic obesity, with adverse influence on quality of survival after craniopharyngioma (10, 14–16). When compared with the general population, craniopharyngioma patients have a 3–19 fold higher cardiovascular mortality (17). In patients initially presenting with hypothalamic involvement of craniopharyngioma, the 20-years overall survival is reduced (13). Regular monitoring by cranial MRI to exclude recurrences are important parts of follow-up care (18).

As an important link between cardiovascular disease and obesity, regional distribution of fat in distinct compartments rather than overall obesity has been postulated. In contrast to subcutaneous adipose tissue, visceral adipose tissue is known as a fat depot, conferring metabolic risk of type 2 diabetes and atherosclerosis above and beyond standard auxiological parameters, such as waist circumference and body mass index (19–21). Upper-body subcutaneous fat, as estimated by neck circumference, may confer risk above and beyond visceral abdominal fat. Serum concentrations of free fatty acid are mainly determined by the upper-body subcutaneous fat compartment, indicating that this compartment plays an important role as specific risk factor for cardiovascular disease (22). We could previously show that nuchal skinfold thickness (NST) – as assessed in MRI of craniopharyngioma patients – serves as a predictor of metabolic risk above and beyond waist circumference and BMI in craniopharyngioma patients (23–27).

In the present study, we analyzed NST as a potential new parameter for assessment of nuchal adipose tissue and its associations with other conventional parameters for assessment of body mass and adipose tissue in long-term survivors of pediatric brain tumor.

Metabolic syndrome consisting of insulin resistance and a minimum of two other risk factors from increased BMI, elevated blood pressure, hypertriglyceridemia, low serum HDL-cholesterol, and microalbuminuria, can result in cardiovascular disease. Obese children have an increased risk of metabolic syndrome, due to their large compartment of fat tissue when compared with children with normal body mass (35–38). There are several distinct fat tissue compartments (subcutaneous adipose tissue, visceral adipose tissue, white adipose tissue present intramuscularly, and brown adipose tissue commonly found in the supraclavicular and subscapular regions) are known with different metabolic characteristics (39). Our study was focused on nuchal adipose tissue, which has been described as a risk factor for metabolic syndrome and has a strong association with the risk of cardiovascular disease (23, 24).

MRI is the gold standard to quantify compartments of different adipose tissue. However, MRI is an expensive method to be performed for this purpose alone. The value and feasibility of auxiological parameters for risk prediction of metabolic syndrome and cardiovascular disease have been analyzed by several studies. In a study of adults, where the visceral adipose tissue on MRI was used as reference, waist circumference correlated better with visceral adipose tissue than BMI, which seemed to be more associated with total adipose tissue (40, 41). A study of Koren et al. (42) showed that in adolescents the sagittal abdominal diameter, which represents abdominal thickness at waist level in supine position, was a better predictor of visceral adipose tissue than waist-to-hip ratio, waist circumference, and BMI. Although in adults the waist-to-hip ratio is associated with cardiovascular disease and type 2 diabetes, this association is less clear in the pediatric age group, most likely due to changes in distribution of body fat during growth (43, 44). Several studies could show that the ratio of waist circumference to height (waist-to-height ratio) is superior to BMI and waist circumference to predict risks of cardiovascular disease (45–48). In a study of adolescents, waist-to-height ratio was associated with BMI SDS and both waist-to-height ratio and BMI had predictive value for arterial hypertension (34). An advantage of waist-to-height ratio measurement is that waist-to-height ratio does not need adjustment for age: a cut-off value of 0.5 can be used in every age group. This makes waist-to-height ratio usable for comparison in pediatric patients of different age (34, 49).

Preis et al. (23) and Da Silva et al. (50) reported on neck circumference as a new parameter for prediction of cardiovascular disease risk. Preis et al. (23) could show that neck circumference was correlated with both BMI and visceral adipose tissue. After adjustment for visceral adipose tissue, the authors observed that neck circumference was positively correlated with blood pressure and risk factors for cardiovascular disease (23).

Long-term prognosis after pediatric brain tumor disease is frequently impaired by cardiovascular disease (1). Craniopharyngioma patients have a 3–19 fold higher cardiovascular mortality when compared with the general population (17) due to hypothalamic obesity caused by tumor and/or treatment related hypothalamic lesions (10, 13–16). Incidence of cardiovascular disease is also increased in patients with pediatric brain tumor of other histology. However, when obesity rates of patients with a brain tumor different from craniopharyngioma are measured by using BMI, pediatric brain tumor patients were observed to present with BMI levels that were either close to or slightly higher than BMI in the general population (6, 7). In accordance with previous reports (6, 7), we also observed no BMI differences between brain tumor patients and healthy controls in our study. However, patients with WHO grade 1–2 brain tumor presented with higher BMI when compared with WHO grade 3-4 brain tumor patients, indicating that low histological grade of malignancy and different treatment might have impact on body composition.

In our previous study (27), analyzing NST on cranial MRIs of craniopharyngioma patients performed during follow-up monitoring, we reported on NST as a new parameter for body composition assessment. We observed that NST was associated with other parameters of body composition such as BMI, caliper-measured skinfold thickness, and waist-to-height ratio. Furthermore, NST had predictive value for cardiovascular disease risk in craniopharyngioma patients and healthy controls.

In this study, we analyzed NST and its associations with the above mentioned anthropometric parameters not only in larger cohorts of craniopharyngioma and healthy controls, but also in pediatric patients with a brain tumor of different histological diagnosis and grades of malignancy. In cross-sectional analyses, NST correlated with the anthropometric parameters BMI and caliper-measured skinfold thickness and was associated with waist-to-height ratio as a known parameter of visceral adipose tissue in all patient groups and in healthy controls. Craniopharyngioma patients with hypothalamic involvement presented with the highest NST. Furthermore, our observations support previous reports (13, 14) that hypothalamic involvement and hypothalamic lesions are associated with severe obesity in long-term survivors of childhood-onset craniopharyngioma.

The results of our study add to the literature on sequelae after brain tumor disease by reporting on the novel observation that NST is a reliable parameter of nuchal adipose tissue correlating with body mass (BMI SDS, waist-to-height ratio) not only in craniopharyngioma patients but also in patients with a brain tumor of different histology and grade of malignancy. Assessment of NST is easy to perform based on a standardized procedure with high reliability. Limitations of our pilot study are differences with regard to older age of craniopharyngioma patients at the time of study/MRI and the small cohort size of patients with a pediatric brain tumor other than craniopharyngioma, which warrants further analyses of larger age-matched cohorts. A further limitation relates to the fact, that due to the high rate of eating disorders in craniopharyngioma patients fasting blood samples for assessment of other risk factors for cardiovascular disease such as glycemic control or lipid status were not available. Furthermore, assessment of total body adiposity could not be achieved, as no sites on the lower body compartment were assessed. Given that impedance analyses are known to be relatively invalid (from variation due to hydration status and food consumption amongst other factors), standardized procedures for medical imaging such as MRI and dual-energy X-ray absorptiometry (DXA) are preferred for VAT measurement. HOMA-IR and other measures of visceral adiposity (i.e. impedance analyses, abdominal MRI, DXA) could not be evaluated in this study but will be part of future prospective studies in context of the German Craniopharyngioma Registry.

MRI-based assessment of NST is not recommended as a routine clinical procedure for assessment of nuchal adipose tissue in obese patients. However, as cranial MRI plays an important role in routine follow-up monitoring for early detection of recurrent brain tumor disease, measurement of NST could serve as a reliable, standardized and easily determinable parameter for nuchal adipose tissue during follow-up after brain tumor. Based on the high association of NST with conventional parameters of body mass, NST might be a suitable tool for identifying brain tumor patients at risk of post-treatment obesity. Especially with regard to the difficulties in collecting reliable anthropometric data in the multicenter setting of our national registry, NST on MRI provides a promising alternative. Furthermore, we could demonstrate that pediatric patients with a brain tumor of low histological malignancy (WHO grade 1 or 2) and craniopharyngioma patients with hypothalamic involvement are at special risk for obesity.

The datasets generated or analyzed during this study are available from the corresponding author on reasonable request.

The studies involving human participants were reviewed and approved by Ethical committee of the medical faculty of the Carl von Ossietzky University, European Medical School (EMS), Oldenburg, Germany. The patients/participants provided their written informed consent to participate in this study.

JP researched the data and wrote the manuscript. SB collected the data and prepared statistical analyses, contributed to the analytical plan and discussion and reviewed/edited the manuscript. ME performed all statistical analyses, contributed to the analytical plan and discussion and reviewed/edited the manuscript. BB did neuroradiological assessment of all imaging. BB was the neuroradiologist, who performs reference-assessment of imaging in all patients recruited in KRANIOPHARYNGEOM 2000/2007. She prepared the imaging data and their presentation and reviewed/edited the manuscript. PS, and CF contributed to the analytical plan and discussion and reviewed/edited the manuscript. HM initiated and conducted the multicenter trials KRANIOPHARYNGEOM 2000 and KRANIOPHARYNGEOM 2007, contributed to the analytical plan and discussion and reviewed/edited the manuscript. Assessments of NST were performed in triplicate (by JP, SB, and HM) for each patient.

This study was funded by grants (HM, DKS2014.13, BB, DKS2018.02) of the German Childhood Cancer Foundation, Bonn, Germany.

HM has received reimbursement of participation fees for scientific meetings and continuing medical education events from the following companies: Ferring, Lilly, Pfizer, Sandoz/Hexal, Novo Nordisk, IPSEN, and Merck Serono. He has received reimbursement of travel expenses from IPSEN and lecture honoraria from Pfizer.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.